Halichondrins, such as Halichondrin B, are anticancer agents originally isolated from the marine sponge Halichondria okadai (See, e.g., D. Uemura et al. “Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge” J. Am. Chem. Soc., 107, 4796 (1985)), and subsequently found in Axinella sp., Phakellia carteri, and Lissondendryx sp. A total synthesis of Halichondrin B was published in 1992 (See, e.g., Y. Kishi et al. “Total Synthesis of Halichondrin B and Norhalichondrin B” J. Am. Chem. Soc., 114, 3162 (1992)). Halichondrin B has demonstrated in vitro inhibition of tubulin polymerization, microtubule assembly, beta 5-tubulin crosslinking, GTP and vinblastine binding to tubulin, and tubulin-dependent GTP hydrolysis, and has shown in vitro and in vivo anti-cancer properties (See, e.g., Y. Hirata et al. “Halichondrins-antitumor polyether macrolides from a marine sponge” Pure Appl. Chem., 58, 701 (1986); Fodstad et al. “Comparative antitumor activities of halichondrins and vinblastine against human tumor xenografts” J. of Experimental Therapeutics & Oncology 1996; 1: 119, 125).
Eribulin mesylate (Halaven™), which was developed based on Halichondrin B (See, e.g., International Publication No. WO 1999/065894, published Dec. 23, 1999; International Publication No. WO 2005/118565, published Dec. 15, 2005; and W. Zheng et al. “Macrocyclic ketone analogues of halichondrin B” Bioorganic & Medicinal Chemistry Letters 14, 5551-5554 (2004)), is currently in clinical use in many countries for the treatment of, e.g., metastatic breast cancer and advanced liposarcoma.
Additional patent publications describing Halichondrins include U.S. Pat. No. 5,436,238 to Kishi, et al., issued Jul. 25, 1995; U.S. Pat. No. 5,338,865 to Kishi, et al., issued Aug. 16, 1994; and WO 2016/003975 filed by Kishi, et al., all of which are assigned to the President and Fellows of Harvard College.
See also, e.g., U.S. Pat. No. 5,786,492; U.S. Pat. No. 8,598,373; U.S. Pat. No. 9,206,194; U.S. Pat. No. 9,469,651; WO/2009/124237A1; WO/1993/017690A1; WO/2012/147900A1; U.S. Pat. No. 7,982,060; U.S. Pat. No. 8,618,313; U.S. Pat. No. 9,303,050; U.S. Pat. No. 8,093,410; U.S. Pat. No. 8,350,067; U.S. Pat. No. 8,975,422; U.S. Pat. No. 8,987,479; U.S. Pat. No. 8,203,010; U.S. Pat. No. 8,445,701; U.S. Pat. No. 8,884,031; U.S. Pat. No. RE45,324; U.S. Pat. No. 8,927,597; U.S. Pat. No. 9,382,262; U.S. Pat. No. 9,303,039; WO/2009/046308A1; WO/2006/076100A3; WO/2006/076100A2; WO/2015/085193A1; WO/2016/176560A1; U.S. Pat. No. 9,278,979; U.S. Pat. No. 9,029,573; WO/2011/094339A1; WO/2016/179607A1; WO/2009/064029A1; WO/2013/142999A1; WO/2015/066729A1; WO/2016/038624A1; and WO/2015/000070A1.
Cancer associated fibroblasts (CAFs), which are widely found in a variety of solid tumors, are stromal cells. It is well known that CAFs play an important role in angiogenesis, invasion, and metastasis. It is reported that there is a close correlation between the amounts of CAFs and clinical prognosis in, for example, invasive breast cancer (See, e.g., M. Yamashita et al. “Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome” Breast Cancer 19, 170, 2012) and esophageal adenocarcinoma (See, e.g., T. J. Underwood et al. “Cancer-associated fibroblasts predict poor outcome and promote periostin-dependent invasion in esophageal adenocarcinoma” Journal of Pathol., 235, 466, 2015). It has also been reported that CAFs correlate to resistance in a variety of tumors such as, for example, breast cancer (See, e.g., P. Farmer et al. “A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer” Nature Medicine., 15(1), 68, 2009), and head and neck cancer (See, e.g., S. Schmitz et al. “Cetuximab promotes epithelial to mesenchymal transition and cancer associated fibroblasts in patients with head and neck cancer” Oncotarget, 6 (33), 34288, 2015; Y. Matsuoka et al. “The tumor stromal features are associated with resistance to 5-FU-based chemoradiotherapy and a poor prognosis in patients with oral squamous cell carcinoma” APMIS 123(3), 205, 2015).
It has thus been observed that tumor vascular remodeling effects and anti-CAF activity result in the improvement of the cancer microenvironment, which assists tumor treatment. Blood vessels are essential for the growth of tumors. Reconstructed blood vessels in tumors can deliver anti-cancer agents to the tumors, in addition to achieving alleviation of hypoxia. It is reported that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits (See, e.g., Y. Funahashi et al. “Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models” Cancer Sci. 105 (2014), 1334-1342). Anti-cancer drugs having tumor vascular remodeling effects and anti-CAF activities have not been reported as of today.
Despite the progress made, additional compounds are needed to progress research and medical care of tumors and cancer.